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Steady-state regulation of whole-body T3 and T4 distribution and metabolism were directly evaluated and compared in hypothyroid, euthyroid, and in euthyroid rats moderately T3-stimulated by continuous infusion of 0.15 microg/day L-T3 per 100 g BW, thereby supplementing euthyroid T3 sources by two thirds. Our goal was to develop deeper insights into the hierarchy, quantitative adequacy, and sensitivity of this regulatory system, in response to these hormone production challenges in constant steady state. We used a novel whole-body steady-state experiment design model and data analysis approach, which entails nonexclusive whole-body homogenate extracts and blood collected after 7-day infusions of tracer T3 (T3*) or T4*, quantitatively analyzed chromatographically for T3*, T4* and metabolite* concentrations. Hormone regulation implications across the 3 groups were assessed by comparing (per 100g BW) total body T4 to T3 and T3 from T4 conversion rates (CR(4-3) and CR(3-4)), total body pool sizes (Qtot) and distribution volumes (V(D)), total body production (PR), or plasma appearance rates (PAR), plasma clearance rates (PCR), and elimination rates (k). In the hypothyroid rats, absolute production of T3 from T4 was only a fourth of that in euthyroids: CR(3-4) = 1.55 vs. 6.77 ng/h, but the percent (efficiency) of whole-body T4 converted to T3 was more than double that in euthyroids: %CR(4-3) = 45.4% vs. 21.0%, reflecting an effective doubling of type I and/or type II 5'-deiodinase activity on a whole-body basis in response to severe curtailment of thyroidal production. Whole-body T3 pools and T3 production and clearance rates were all about 2 to 3 times lower in hypo- than in euthyroids: minimum Qtot = 36.8 vs. 100 ng, V(D3) = 148 vs. 236 ml, PAR3 = 3.44 vs. 9.09 ng/h, PCR3 = 13.8 vs. 21.3 ml/h; and nearly all T4 pool size, production, clearance and elimination rates also were very substantially reduced: PCR4 = 0.540 vs. 0.941 ml/h, PR4 = 4.11 vs. 38.3 ng/h, Qtot4 = 128 vs. 702 ng, k4 = 0.0322 vs. 0.0530 h(-1). In moderately T3-stimulated rats, presumed central feedback effects of the added T3 on T4 production and total body pool size also were quite pronounced: PR4 = 21.4 ng/h and Qtot4 = 346 ng were reduced to about half that in euthyroids, but T4 elimination indices were virtually unchanged, and T3 production and elimination were minimally affected. Thus, overall, stabilizing negative feedback regulation of TH functioning at different hierarchical levels is quite bidirectionally sensitive. We found very tight (inhibitory) control over thyroidal T4 secretion, possibly also T3 secretion, and probably also absolute T3 production from T4, in response to moderate (+68%) supplements in T3 production; and the efficiency of total body T3 production from available T4 was amplified substantially in the severe primary hypothyroid state, although not nearly enough to compensate for the malady. Finally, the blood to total body pool fractions (Qb/Qtot) of both T3 and T4, but not the plasma or blood hormone levels, remained remarkably constant in response to these oppositely directed hormone production challenges, suggesting this ratio as an actively regulated, homeostatically-maintained entity.

Steady-state regulation of whole-body thyroid hormone pool sizes and interconversion rates in hypothyroid and moderately T3-stimulated rats.